Identification and targeting of metastatic biomarkers for hepatocellular carcinoma therapeutics using small molecules library of curcumin analogues.

The understanding of the molecular basis of complex diseases like hepatocellular carcinoma (HCC) needs large datasets of multiple genes and proteins involved in different phenomenon of its development. This study focuses on the molecular basis of HCC and the development of therapeutic strategies. We analyzed a dataset of 5475 genes (Homo sapiens) involved in HCC hallmarks, involving comprehensive data on multiple genes and frequently mutated genes. As HCC is characterized by metastasis, angiogenesis, and oxidative stress, exploration of genes associated with them has been targeted. Through gene ontology, functional characterization, and pathway enrichment analysis, we identified target proteins such as Lysyl oxidase, Survivin, Cofilin, and Cathepsin B. A library of curcumin analogs was used to target these proteins. Tetrahrydrocurcumin showed promising binding affinities for all four proteins, suggesting its potential as an inhibitor against these proteins for HCC therapy.

The cross-talk between mucormycosis, steroids and diabetes mellitus amidst the global contagion of COVID-19.

Mucormycosis is an opportunistic fungal disease that targets individuals having an impaired immune system due to a wide array of risk factors including HIV-AIDS, immunosuppressive therapy, diabetes mellitus, etc. The current explosive outbreak of coronavirus disease 2019 (COVID-19) has become the latest threat to such patients who are already susceptible to secondary infections. Physiological outcomes of COVID-19 end up in a cascade of grave alterations to the immunological profile and irreparable harm to their respiratory passage, heart and kidneys. Corticosteroidal treatment facilitates faster recovery and alleviates the adverse pathological effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). But clinical reports lend this approach a darker perspective especially if these patients have pre-existing diabetes mellitus. The mucormycotic fungal genera belonging to the order Mucorales not only survive but thrive under the comorbidity of COVID-19 and diabetes, often staying undetected until they have inflicted irreversible damage. Steroidal usage has been noted to be a common thread in the sudden spurt in secondary fungal infections among COVID-19 cases. Once considered a rare occurrence, mucormycosis has now acquired a notoriously lethal status in mainstream medical hierarchy. We set out to investigate whether corticosteroidal therapy against COVID-19 emboldens the development of mucormycosis. We also assess the conditions brought forth by steroidal usage and uncontrolled progression of diabetes in COVID-19 cases and their effect on the susceptibility towards mucormycosis.

Epigenetic Diversity Underlying Seasonal and Annual Variations in Brown Planthopper (BPH) Populations as Revealed by Methylation- sensitive Restriction Assay.

Background: The brown planthopper (BPH) is a monophagous sap-sucking insect pest of rice that is responsible for massive yield loss. BPH populations, even when genetically homogenous, can display a vast range of phenotypes, and the development of effective pest-management strategies requires a good understanding of what generates this phenotypic variation. One potential source could be epigenetic differences. Methods: With this premise, we explored epigenetic diversity, structure and differentiation in field populations of BPH collected across the rice-growing seasons over a period of two consecutive years. Using a modified methylation-sensitive restriction assay (MSRA) and CpG island amplification-representational difference analysis, site-specific cytosine methylation of five stress-responsive genes (CYP6AY1, CYP6ER1, Carboxylesterase, Endoglucanase, Tf2-transposon) was estimated, for identifying methylation-based epiallelic markers and epigenetic variation across BPH populations. Results: Using a cost-effective and rapid protocol, our study, for the first time, revealed the epigenetic component of phenotypic variations in the wild populations of BPH. Besides, results showed that morphologically indistinguishable populations of BPH can be epigenetically distinct. Conclusion: Screening field-collected BPH populations revealed the presence of previously unreported epigenetic polymorphisms and provided a platform for future studies aimed at investigating their significance for BPH. Furthermore, these findings can form the basis for understanding the contribution(s) of DNA methylation in providing phenotypic plasticity to BPH.

Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action.

Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune-related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use.

Infestation of Rice by Gall Midge Influences Density and Diversity of Pseudomonas and Wolbachia in the Host Plant Microbiome.

Background: The virulence of phytophagous insects is predominantly determined by their ability to evade or suppress host defense for their survival. The rice gall midge (GM, Orseolia oryzae), a monophagous pest of rice, elicits a host defense similar to the one elicited upon pathogen attack. This could be due to the GM feeding behaviour, wherein the GM endosymbionts are transferred to the host plant via oral secretions, and as a result, the host mounts an appropriate defense response(s) (i.e., up-regulation of the salicylic acid pathway) against these endosymbionts. Methods: The current study aimed to analyze the microbiome present at the feeding site of GM maggots to determine the exchange of bacterial species between GM and its host and to elucidate their role in rice-GM interaction using a next-generation sequencing approach. Results: Our results revealed differential representation of the phylum Proteobacteria in the GM-infested and -uninfested rice tissues. Furthermore, analysis of the species diversity of Pseudomonas and Wolbachia supergroups at the feeding sites indicated the exchange of bacterial species between GM and its host upon infestation. Conclusion: As rice-GM microbial associations remain relatively unstudied, these findings not only add to our current understanding of microbe-assisted insect-plant interactions but also provide valuable insights into how these bacteria drive insect-plant coevolution. Moreover, to the best of our knowledge, this is the first report analyzing the microbiome of a host plant (rice) at the feeding site of its insect pest (GM).

Network pharmacological evaluation of strigolactones efficacy as potential inhibitors against therapeutic targets of hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is the uncontrolled growth of hepatocytes which results in nearly 5 million deaths worldwide. Specific strategies have been developed to treat HCC, including surgery, chemotherapy and radiotherapy. But, the effective disease dealing requires synergistic collaboration with other approaches, which often results in moderate to severe side effects during and after the treatment period. Therefore, the focus is now shifting to explore and retrieve those plant-based products that could be utilized to treat HCC with maximum efficacy without causing any side effects. Strigolactones (SL) are compounds of plant origin derived from Striga lutea responsible for controlling the branching pattern of stem and have reported anti-cancerous activity by promoting apoptosis at micromolar concentrations. However, little work has been done concerning determining the pharmacogenomic effect of strigolactones on HCC. METHODS: Current work focuses on comparing therapeutic efficiencies of SL analogs against core targets of HCC using network pharmacology approach, pharmacokinetics analysis, gene ontogeny, functional enrichment analysis, molecular docking and Molecular Dynamics simulation. RESULTS: Drug-target prediction and functional enrichment analysis showed that HDAC1 and HDAC2 are the core proteins involved in hepatocellular carcinoma that strigolactone analogs can target. Consequently, results from molecular docking and MD simulation analyses report that among all the SL analogs strigol, epistrigol and nijmegen1 can turn out to be most effective in downregulating the expression of HDAC1, HDAC2 and CYP19A. CONCLUSION: Strigol, epistrigol and nijmegen1 could be used as potential inhibitors against HCC and can be further validated through in vitro/in vivo studies.

Adherence to chronic hepatitis B screening guidelines for persons from intermediate to high prevalence Countries.

The adherence to the CDC guideline on screening non-U.S. born persons for hepatitis B virus infection was assessed. A retrospective cohort study was conducted at University of Washington primary care clinics using the electronic medical records. Persons from hepatitis B virus prevalent countries were identified using country of origin and language. Of 2329 eligible for screening, only 617 (26.5%) were screened. The prevalence of HBsAg was 35 (5.7%). Among women of reproductive age (18-44 years, n = 906), 238 (26.3%) were screened, and 7 (2.9%) were HBsAg positive. Low screening practice for chronic hepatitis B infection, and high infection prevalence among those screened was noted. The findings indicate that potentially three out of every one detected case may be missed. Urgent efforts are needed to scale up and consistently implement HBV screening at primary care clinics.

Cervical cancer screening, abnormal results, and follow-up in women with substance use-related diagnoses.

Background: Substance use-related diagnoses are common and associated with poor health outcomes. The objective of this analysis was to compare rates of cervical cancer screening, screening abnormalities, and follow-up care in women with and without a substance use-related diagnosis seen for primary care between January 1, 2016 and December 31, 2019 in the University of Washington healthcare system. Methods: This study included women aged 21-65 years of age who had at least one outpatient visit between January 1, 2016 and December 31, 2019 within one of 45 primary care or women's health clinics in the academic healthcare system. Exposure status was defined using ICD10 codes for substance-use related diagnoses or no substance-use related diagnoses. Only first cervical cancer screening was included. Generalized linear models with a binomial family and log link were used to estimate risk ratios. Results: 3845 women had a substance use-related diagnosis and 89214 did not. Women with a substance use-related diagnosis were less likely to be screened for cervical cancer (44%, 1675/3845) compared to women without a substance use-related diagnosis (49%, 43338/89214; relative risk [RR] 0.90, 95% CI 0.86-0.93). Women with a substance use-related diagnosis were also more likely to have an abnormal screening result (18%, 304/1675) compared to women without a substance use-related diagnosis (10%, 4528/43338; RR 1.74, 95% CI 1.56-1.93). Follow-up for abnormal screens did not differ significantly between groups (24 vs 25%; RR 0.80, 95% CI 0.55-1.17). Conclusion: To combat disparities in cervical cancer screening for women with substance use-related diagnoses, public health efforts should expand access to screening where women with substance use-related diagnoses are seen, including acute care, inpatient hospitalizations, and addiction treatment settings.

Methylation patterns of Tf2 retrotransposons linked to rapid adaptive stress response in the brown planthopper (Nilaparvata lugens).

Transposable elements (TEs) exhibit vast diversity across insect orders and are one of the major factors driving insect evolution and speciation. Presence of TEs can be both beneficial and deleterious to their host. While it is well-established that TEs impact life-history traits, adaptations and survivability of insects under hostile environments, the influence of the ecological niche on TE-landscape remains unclear. Here, we analysed the dynamics of Tf2 retrotransposons in the brown planthopper (BPH), under environmental fluctuations. BPH, a major pest of rice, is found in almost all rice-growing ecosystems. We believe genome plasticity, attributed to TEs, has allowed BPH to adapt and colonise novel ecological niches. Our study revealed bimodal age-distribution for Tf2 elements in BPH, indicating the occurrence of two major transpositional events in its evolutionary history and their contribution in shaping BPH genome. While TEs can provide genome flexibility and facilitate adaptations, they impose massive load on the genome. Hence, we investigated the involvement of methylation in modulating transposition in BPH. We performed comparative analyses of the methylation patterns of Tf2 elements in BPH feeding on resistant- and susceptible-rice varieties, and also under pesticide stress, across different life-stages. Results confirmed that methylation, particularly in non-CG context, is involved in TE regulation and dynamics under stress. Furthermore, we observed differential methylation for BPH adults and nymphs, emphasising the importance of screening juvenile life-stages in understanding adaptive-stress-responses in insects. Collectively, this study enhances our understanding of the role of transposons in influencing the evolutionary trajectory and survival strategies of BPH across generations.

Heritable Epigenomic Modifications Influence Stress Resilience and Rapid Adaptations in the Brown Planthopper (Nilaparvata lugens).

DNA methylation in insects is integral to cellular differentiation, development, gene regulation, genome integrity, and phenotypic plasticity. However, its evolutionary potential and involvement in facilitating rapid adaptations in insects are enigmatic. Moreover, our understanding of these mechanisms is limited to a few insect species, of which none are pests of crops. Hence, we studied methylation patterns in the brown planthopper (BPH), a major rice pest, under pesticide and nutritional stress, across its life stages. Moreover, as the inheritance of epigenetic changes is fundamentally essential for acclimation, adaptability, and evolution, we determined the heritability and persistence of stress-induced methylation marks in BPH across generations. Our results revealed that DNA methylation pattern(s) in BPH varies/vary with environmental cues and is/are insect life-stage specific. Further, our findings provide novel insights into the heritability of stress-induced methylation marks in BPH. However, it was observed that, though heritable, these marks eventually fade in the absence of the stressors, thereby suggesting the existence of fitness cost(s) associated with the maintenance of the stressed epigenotype. Furthermore, we demonstrate how 5-azacytidine-mediated disruption of BPH methylome influences expression levels of stress-responsive genes and, thereby, highlight demethylation/methylation as a phenomenon underlying stress resilience of BPH.

FlavorDB: a database of flavor molecules.

Flavor is an expression of olfactory and gustatory sensations experienced through a multitude of chemical processes triggered by molecules. Beyond their key role in defining taste and smell, flavor molecules also regulate metabolic processes with consequences to health. Such molecules present in natural sources have been an integral part of human history with limited success in attempts to create synthetic alternatives. Given their utility in various spheres of life such as food and fragrances, it is valuable to have a repository of flavor molecules, their natural sources, physicochemical properties, and sensory responses. FlavorDB (http://cosylab.iiitd.edu.in/flavordb) comprises of 25,595 flavor molecules representing an array of tastes and odors. Among these 2254 molecules are associated with 936 natural ingredients belonging to 34 categories. The dynamic, user-friendly interface of the resource facilitates exploration of flavor molecules for divergent applications: finding molecules matching a desired flavor or structure; exploring molecules of an ingredient; discovering novel food pairings; finding the molecular essence of food ingredients; associating chemical features with a flavor and more. Data-driven studies based on FlavorDB can pave the way for an improved understanding of flavor mechanisms.

Use of Dynamic MRI of the Pelvic Floor in the Assessment of Anterior Compartment Disorders.

PURPOSE OF REVIEW: Approximately 25% of women in the USA suffer from pelvic floor disorders. Disorders of the anterior compartment of the pelvic floor, in particular, can cause symptoms such as incomplete urinary voiding, urinary incontinence, pelvic organ prolapse, dyspareunia, and pelvic pain, potentially negatively impacting a woman's quality of life. In some clinical situations, clinical exam alone may be insufficient, especially when patient's symptoms are in excess of their pelvic exam findings. In many of these patients, dynamic magnetic resonance imaging (dMRI) of the pelvic floor can be a valuable imaging tool allowing for comprehensive assessment of the entire pelvic anatomy and its function. RECENT FINDINGS: Traditionally, evaluation of the anterior compartment has been primarily through clinical examination with occasional use of urodynamic testing and ultrasound. In recent years, dMRI has continued to gain popularity due to its improved imaging quality, reproducibility, and ability to display the entire pelvic floor. Emerging evidence has also shown utility of dMRI in the postoperative setting. In spite of advances, there remains an ongoing discussion in contemporary literature regarding the accuracy of dMRI and its correlation with clinical examination and with patient symptoms. Dynamic pelvic MRI is a helpful adjunct to physical examination and urodynamic testing, particularly when a patient's symptoms are in excess of the physical examination findings. Evaluation with dMRI can guide preoperative and postoperative surgical management in many patients, especially in the setting of multicompartmental disorders. This review will summarize relevant pelvic floor anatomy and discuss the clinical application, imaging technique, imaging interpretation, and limitations of dMRI.

Prevention of IcaA regulated poly N-acetyl glucosamine formation in Staphylococcus aureus biofilm through new-drug like inhibitors: In silico approach and MD simulation study.

OBJECTIVES: The effectiveness of various ligands against the protein structure of IcaA of the IcaABCD gene locus of Staphylococcus aureus were examined using the approach of structure based drug designing in reference with the protein's efficiency to form biofilms. RESULTS: Four compounds CID42738592, CID90468752, CID24277882, and CID6435208 were secluded from a database of 31,242 inhibitory ligands on the justification of the evaluated values falling under the four - tier structure based virtual screening. Under this principle value of least binding energy, human oral absorption and ADME properties were taken into consideration. Using the Glide module of Schrödinger, the above mentioned ligands showed an effective action against the protein IcaA which showed reduced activity as a glucosaminyl transferase. The complex of protein and ligand with best docking score was chosen for simulation studies. CONCLUSIONS: Structure based drug designing for the protein IcaA has given us potential leads as anti - biofilm agents. These screened out ligands might enable the development of new therapeutic strategies aimed at disrupting Staphylococcus aureus biofilms. The complex was showing stability towards the end of time for which it has been put for simulation. Thus molecule could be considered for making of biofilms.

Comparison between intranasal dexmedetomidine and intranasal midazolam as premedication for brain magnetic resonance imaging in pediatric patients: A prospective randomized double blind trial.

BACKGROUND AND AIMS: Preprocedural preparation of children scheduled for magnetic resonance imaging (MRI) is challenging. This prospective, randomized trial compared intranasal midazolam with intranasal dexmedetomidine as premedication for children scheduled for brain MRI. MATERIAL AND METHODS: In total, 60 children, aged 1-8 years, scheduled for elective brain MRI, were randomly assigned to the intranasal dexmedetomidine (1 µg/kg; Group D) or intranasal midazolam (0.2 mg/kg; Group M) group. We compared hemodynamic and respiratory parameters, onset, level, sedation quality, and successful parental separation. All patients received intravenous propofol as an induction and maintenance agent for MRI. RESULTS: No significant differences were observed in demographic, hemodynamic, and respiratory parameters. Group D (14.3 ± 3.4 min [10-20 min]) had a longer time of sedation onset than Group M (8.7 ± 3.7 min [5-15 min]; P < 0.001). The median and mean sedation scores were lower in Group D (3 and 3.7 ± 0.8, respectively) than Group M (4 and 4.3 ± 1.2, respectively; P = 0.055). Group D (80%) had a higher percentage of children achieving satisfactory sedation at the time of induction than did Group M (53.3%; P = 0.0285). Parental separation was successful in 73.3% of patients in Group D compared with 46.7% of patients in Group M (P = 0.035). CONCLUSION: Intranasal dexmedetomidine results in more successful parental separation and yields a higher sedation level at the time of induction of anesthesia than intranasal midazolam as premedication, with negligible side effects. However, its onset of action is relatively prolonged.

To breathe or not to breathe: a review of artificial airway placement and related complications.

Artificial airway devices are commonly used to provide adequate ventilation and/or oxygenation in multiple clinical settings, both emergent and nonemergent. These frequently used devices include laryngeal mask airway, esophageal-tracheal combitube, endotracheal tube, and tracheostomy tube and are associated with various acute and late complications. Clinically, this may vary from mild discomfort to a potentially life-threatening situation. Radiologically, these devices and their acute and late complications have characteristic imaging findings which can be detected primarily on radiographs and computed tomography. We review appropriate positioning of these artificial airway devices and illustrate associated complications including inadequate positioning of the endotracheal tube, pulmonary aspiration, tracheal laceration or perforation, paranasal sinusitis, vocal cord paralysis, post-intubation tracheal stenosis, cuff overinflation with vascular compression, and others. Radiologists must recognize and understand the potential complications of intubation to promptly guide management and avoid long-term or even deadly consequences.

C-reactive protein and procalcitonin: As predictor biomarkers of severity and outcome in children with community-acquired pneumonia.

Our cohort study aimed to compare serum C-reactive protein (CRP) and procalcitonin (PCT) levels in children with community-acquired pneumonia defined by WHO. The former differentiated between pneumonia and severe pneumonia while the latter was better for the outcome of pneumonia.

Comparative evaluation of divergent concoction of NGF, BDNF, EGF, and FGF growth factor's role in enhancing neuronal differentiation of adipose-derived mesenchymal stem cells.

MSCs (Mesenchymal Stem Cells) can differentiate into various lineages, including neurons and glial cells. In the past few decades, MSCs have been well explored in the context of neuronal differentiation and have been reported to have the immense potential to form distinct kinds of neurons. The distinguishing features of MSCs make them among the most desired cell sources for stem cell therapy. This study involved the trans-differentiation of Adipose-derived human Mesenchymal Stem Cells (ADMSCs) into neurons. The protocol employs a cocktail of chemical inducers in different combinations, including Brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), and Nerve growth factor (NGF) Fibroblastic growth factor (FGF), in induction media. Both types have been successfully differentiated into neurons, confirmed by morphological aspects and the presence of neural-specific markers through RT-PCR (Reverse transcription polymerase chain reaction) studies and immunocytochemistry assay. They have shown excellent morphology with long neurites, synaptic connections, and essential neural markers to validate their identity. The results may significantly contribute to cell replacement therapy for neurological disorders.

Pseudomonas-specific 16S rRNA insect gut-microbiome profiling using next-generation sequencing.

We present a detailed protocol for Pseudomonas-specific 16S rRNA gut-microbiome profiling of brown planthopper (BPH) populations collected across changing climates and geographical locations using next-generation sequencing. We provide a technique for comparative analysis of Pseudomonas species structure and composition across BPH populations. Additionally, using qPCR we quantify the titers of Pseudomonas species in BPH. This protocol can be adopted for analyzing microbiome dynamics and monitoring populations of other pests, a crucial aspect for understanding their biodiversity, speciation, and adaptations. For complete details on the use and execution of this protocol, please refer to Gupta et al. (2022).1.

Therapeutical growth in oligodendroglial fate induction via transdifferentiation of stem cells for neuroregenerative therapy.

The merits of stem cell therapy and research are undisputed due to their widespread usage in the treatment of neurodegenerative diseases and demyelinating disorders. Cell replacement therapy especially revolves around stem cells and their induction into different cell lineages both adult and progenitor - belonging to each germ layer, prior to transplantation or disease modeling studies. The nervous system is abundant in glial cells and among these are oligodendrocytes capable of myelinating new-born neurons and remyelination of axons with lost or damaged myelin sheath. But demyelinating diseases generate tremendous deficit between myelin loss and recovery. To compensate for this loss, analyze the defects in remyelination mechanisms as well as to trigger full recovery in such patients mesenchymal stem cells (MSCs) have been induced to transdifferentiate into oligodendrocytes. But such experiments are riddled with problems like prolonged, tenuous and complicated protocols that stretch longer than the time taken for the spread of demyelination-associated after-effects. This review delves into such protocols and the combinations of different molecules and factors that have been recruited to derive bona fide oligodendrocytes from in vitro differentiation of embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and MSCs with special focus on MSC-derived oligodendrocytes.

Modulation of GPCR receptors common to gut inflammatory diseases and neuronal disorders, Alzheimer's and Parkinson's diseases as druggable targets through Withania somnifera bioactives: an in silico study.

Microorganisms in human gastrointestinal tract have profound influence on the transformation of food into metabolites which can impact human health. Along with playing crucial roles in regulating and modulating various metabolic reactions and life processes, dysbiosis of gut microbiota also affects the permeability of gut and blood-brain barrier. This increases the chance of age-related neurological disorders' like Alzheimer's and Parkinson's diseases. Withania somnifera (W. somnifera) has been proclaimed as a virtuous plant for the treatment of neurodegenerative diseases and many other problems. We have studied the bioactive components of W. somnifera for combined treatment of gut-dysbiosis led bowel diseases (Inflammatory Bowel Disease, Irritable Bowel Syndrome) and the most common neurodegenerative diseases through common potential targets. This approach can solve along with curing the neurodegenerative diseases, the factors causing these diseases would also be obstructed from entering the brain, consonantly curing Inflammatory Bowel Disease and Irritable Bowel Syndrome. Our work on GPCR receptors common to gut inflammatory diseases and neuronal disorders through Network Pharmacology, Molecular docking and Dynamic Simulation approach has shown that modulation of these receptors with bioactive compounds present in W. somnifera can result in effective control of these diseases. We have found five proteins (HTR1A, HTR1B, HTR2A, HTR2B & HTR7) and five best lead compounds (Withanolide A, B, E, Q & Anahygrine) against these targets after molecular docking analysis. Our simulation studies have finally shown that amongst these five HTR1A and HTR7 proteins are the best targets with the leads Withanolide E and Withanolide A against them, respectively.Communicated by Ramaswamy H. Sarma.